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Apr 24, 2014

Genome-Preserving, Cancer-Preventing Enzyme Pathway Found

Genome-Preserving, Cancer-Preventing Enzyme Pathway Found

A model of the enzyme Cdc14. Red areas have identical amino acid sequences in human and yeast Cdc14. The ideal "key," or substrate, that would fit into Cdc14 is marked by the green and blue structure nestled into a "lock." [Molecular Cell/Mark Hall]

  • In processes such as cell division, enzymatic events succeed each other like so many dominoes. If, for whatever reason, a domino were to go missing, the consequences could be catastrophic. In the case of one newly discovered enzyme pathway, the dominoes must fall just so—otherwise a parent cell may divide into daughter cells that receive too many or too few chromosomes. And if that happens, the result can be cancer.

    The string of dominoes that falls during cell division includes enzymes responsible for DNA damage detection and repair. One such enzyme, Cdc14, has been linked to DNA damage repair in humans, but exactly how the enzyme helps preserve the genome and which proteins it regulates in this process remained obscure—at least until researchers at Purdue University took a closer look.

    A research team led by Purdue’s Mark Hall, Ph.D., found that near the end of cell division, Cdc14 activates Yen1, an enzyme that ensures any breaks in DNA are fully repaired before the parent cell distributes copies of the genome to daughter cells. This process helps safeguard against some of the most devastating genome errors, including the loss of chromosomes or chromosome segments.

    To secure this finding, Dr. Hall and his fellow researchers developed a method to identify the protein substrates upon which Cdc14 acts. Cdc14 regulates the function of other proteins by removing phosphate from them. Using Cdc14 in baker’s yeast, which is very similar to human Cdc14, the team studied the activity of the enzyme on a wide variety of synthetic substrate molecules, looking for similar features among the molecules most preferred by Cdc14.

    “We were basically trying different keys in the lock to see which would fit the best,” Dr. Hall said.
    The team identified the most common structural features on molecules targeted by Cdc14 and used bioinformatics tools to pinpoint matching features in yeast proteins. Yen1 proved to be the best match, and further tests confirmed its role as a substrate of Cdc14. Yen1 is the first Cdc14 substrate involved in DNA repair to be identified.

    The details of the team’s work appeared April 10 in Molecular Cell, in an article entitled “The Cdk/Cdc14 Module Controls Activation of the Yen1 Holliday Junction Resolvase to Promote Genome Stability.”

    As the article’s title indicates, the Cdc14/Yen1 interaction is only part of the story. In particular, as the study’s authors indicated, Cdk phosphorylation restrains Yen1 activity to limit mitotic crossovers, and Cdc14 triggers Yen1 activation to ensure proper chromosome segregation.

    “Cdc14 activation at anaphase triggers nuclear accumulation and enzymatic activation of Yen1, likely to resolve persistent recombinational repair intermediates. Consistent with this, expression of a phosphomimetic Yen1 mutant increased sister chromatid nondisjunction,” the authors wrote. “In contrast, lack of Cdk phosphorylation resulted in constitutive activity and elevated crossover-associated repair. The precise timing of Yen1 activation, governed by core cell-cycle regulators, helps coordinate DNA repair with chromosome segregation and safeguards against genome destabilization.

    Dr. Hall added that understanding Cdc14’s role in DNA repair and how the enzyme binds to its substrates could be used to develop more effective chemotherapeutic weapons against cancer. Many chemotherapeutic drugs work by producing such extensive DNA damage in cancer cells that they kill themselves. Designing a chemical that mimics the features of a Cdc14 substrate would help block Cdc14 from repairing damaged DNA in cancer cells, speeding their death.

    “Developing Cdc14 inhibitory compounds could make certain cancer treatments more specific and potent,” Dr. Hall concluded. “You could think of Cdc14 inhibitors as kryptonite to cancer cells, potentially weakening their ability to heal themselves and making them more vulnerable to chemotherapy treatment.”



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